Research Project
10261588
PROJECT SUMMARY/ABSTRACT Exercise capacity, also known as cardiorespiratory fitness, has emerged as one of the single best predictors of health and longevity. Low exercise capacity is a strong risk factor for the development of cardiovascular disease and overall mortality. Aerobic exercise training is the only effective treatment to increase exercise capacity and reduce the health risks associated with low exercise capacity. However, even when levels of physical activity are matched, exercise capacity remains lower in people with metabolic diseases such as Type 1 and Type 2 diabetes compared to those without metabolic disease, suggesting a phenotype of ?low response to training?. The goal of this investigation is to determine the mechanisms that contribute to low response to training in metabolic disease, and develop treatment strategies to improve the response to exercise. Clinical investigations and our data from animal models suggest that chronically high blood glucose levels (i.e. hyperglycemia) may be a cause for low response to training by blunting beneficial adaptations that normally occur with exercise in tissues like skeletal muscle. We hypothesize that hyperglycemia causes glycation and accumulation of the extracellular matrix (ECM) in muscle, and in turn, these glucose-induced ECM alterations can prevent tissue remodeling with exercise in 3 distinct ways: 1) Altering muscle signal transduction via a newly discovered JNK/SMAD mechanical signaling axis; 2) Impairing the function of muscle progenitor and endothelial cells; and 3) Reducing levels of circulating ECM remodeling proteins. One specific aim is to determine whether blood glucose lowering treatments can improve exercise capacity and muscle remodeling in response to exercise in animal models of metabolic disease. A second aim is to determine the cellular and molecular mechanisms in muscle that contribute to low exercise response under conditions of hyperglycemia. Finally, we will use advanced proteomic screening combined with in vitro methodology to identify circulating mediators of low response to training in humans subjects. Hyperglycemia is becoming more common as rates of metabolic disease rise globally. This may lead to a population that is increasingly resistant to improved exercise capacity with training, and the associated reduction in health risk. Despite significant clinical evidence linking chronic hyperglycemia to the ?low-response to training? phenotype, little is known about the molecular mechanisms underlying these associations. This project will significantly advance our understanding of the mechanisms that cause low response to training in people with metabolic disease, and identify treatments to improve exercise capacity, health span, and longevity.
